Duchenne muscular dystrophy (DMD) is a recessively inherited progressive form of muscle-wasting disease affecting ˜1 in 3,000 boys. The reported incidence is 25/100,000 live male births worldwide (Katirji, B., Kaminski, H. J., Preston, D. C., Ruff, R. L., Shapiro, B. E. (2002) Neuromuscular disorders in clinical practice. Butterworth Heinemann). First signs of the disease become apparent when boys start to walk. Muscle wasting occurs initially in proximal and later in distal muscle groups leading to the loss of ambulation in teenage patients. Mutations in the dystrophin gene and absence of dystrophin protein ultimately lead to death of DMD patients at early adulthood, mainly because of respiratory or cardiac failures. Clinical measures to improve quality of life comprise orthopedic surgery and nighttime ventilation. Becker muscular dystrophy (BMD) is caused by different mutations of the same dystrophin gene but has a milder clinical course and the patients have a prolonged life expectancy when compared to DMD patients. Cellular processes underlying DMD-associated muscle wasting include the loss of skeletal muscle fibers and accompanying invasion by connective and adipose tissue. Progressive weakness of the skeletal musculature and cardiac involvement leads to early morbidity and mortality in DMD/BMD patients.
Both DMD and BMD are caused by mutations in the dystrophin gene. The dystrophin gene consists of 2700 kbp and is located on the X chromosome (Xp21.2, gene bank accession number: M18533). The 14 kbp long mRNA transcript is expressed predominantly in skeletal, cardiac and smooth muscle and to a limited extent in the brain. The mature dystrophin protein has a molecular weight of ˜427 kDa and belongs to the spectrin superfamily of proteins (Brown S. C., Lucy J. A. (eds), “Dystrophin”, Cambridge University Press, 1997). While the underlying mutation in DMD leads to a lack of dystrophin protein, the milder BMD-phenotype is a consequence of mutations leading to the expression of abnormal, often truncated, forms of the protein with residual functionality.
X-linked dilated cardiomyopathy (XLDCM) is a progressive and fatal type of heart disease that presents in the second or third decade of life, with congestive heart failure in patients without skeletal muscle weakness (Towbin et al. (1993) X-linked dilated cardiomyopathy; molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at Xp21 locus. Circulation 87:1854-65). Different mutations in the dystrophin gene cause selective absence of dystrophin in heart muscle, whereby mutations involving the 5′ end of the dystrophin gene result in more severe cardiomyopathy than mutations in the spectrin-like region. With mutations involving the 5′ end of the dystrophin gene, the exclusive cardiac involvement seems to be related to a difference in RNA splicing regulation between heart and skeletal muscle. The skeletal muscle maintains dystrophin production by using exon skipping or alternative splicing, whereas the heart muscle is apparently unable to use such mechanisms.
The N-terminal part of dystrophin binds to actin filaments of the cytoskeleton, whereas domains in the C-terminal part of the dystrophin molecule bind to the membrane associated β-dystroglycan. Therefore, dystrophin serves as a molecular linker between the cytoskeleton and the muscle cell membrane and, indirectly, via the so-called dystrophin-associated protein complex (DAPC) also to the extracellular matrix. Known binding partners of dystrophin also include syntrophin, dystrobrevin, the neuronal type nitric oxide synthase (nNOS) and the sarcoglycan-sarcospan (SS) complex. These protein interactions involving both the carboxy- and aminoterminal region of the dystrophin protein are thought to contribute to the mechanical stability of the muscle cell membrane during cycles of contraction and relaxation. Dystrophin is also important for the assembly or integrity of the DAPC-complex itself, as it has been shown that in dystrophin-deficient muscle cells of DMD patients many components of the DAPC complex are reduced or absent in the sarcolemma. Absence of functional dystrophin protein leads to disruption of the mechanical link between actin cytoskeleton and the muscle cell sarcolemma which in turn leads to deterioration of myotubes and muscle weakness (Brown S. C., Lucy J. A. (eds), “Dystrophin”, Cambridge University Press, 1997).
Cardiac involvement is present in almost all DMD patients but a clinical manifestation of cardiac and also gastrointestinal defects occurs late in the course of DMD. In a study on incidence and evolution of cardiomyopathy in 328 DMD patients, Nigro et al. (Nigro, G., Comi, L. I., Politano, L. and Bain, R. J. (1990), (Int J Cardiol, 26, 271-277) showed that the incidence of cardiac involvement increased steadily over the teenage years, with approximately one third of the patients being affected by the age of 14, one half of the patients by age 18, and all patients older than 18 years. Dilated cardiomyopathy occurs in 40% of the patients and can be life threatening in later stages of the disease. Previously it has been estimated that 10% to 15% of all DMD patients die from cardiac failure caused by dilated cardiomyopathy (Ishikawa, Y., Bach, J. R. and Minami, R. (1999) Cardioprotection for Duchenne's muscular dystrophy. Am Heart J, 137, 895-902). More recently, with the introduction of ventilatory support to treat respiratory failure, congestive heart failure is becoming one of the major causes of death (currently up to 30% of all DMD patients; Finsterer, J. and Stollberger, C. (2003) The heart in human dystrophinopathies. Cardiology, 99, 1-19).
The cardiac involvement in DMD is characterized by degeneration, atrophy and fibrosis of the myocardium, leading to dilated cardiomyopathy. The process begins in the posterolateral wall of the left ventricle (LV), with septal involvement appearing at later stages. Generally, the right ventricle (RV) is not involved. Early in life (below 12 years), cardiac function is usually interpreted as normal using conventional grey-scale echocardiographic techniques (M-Mode and two-dimensional imaging), which are only capable to detect global abnormalities once the myocardial damage is established. Fractional shortening (FS) and ejection fraction (EF) are the most commonly used parameters to assess LV systolic function, whereas mitral blood flow and pulmonary venous flow are measured to assess diastolic function. It has been shown that DMD patients progressively develop echocardiographic signs of LV dysfunction, which are normally detected around the onset of adolescence (Finsterer, J. and Stollberger, C. (2003) The heart in human dystrophinopathies. Cardiology, 99, 1-19; Sasaki K, et al. (1998) Sequential changes in cardiac structure and function in patients with Duchenne type muscular dystrophy: a two-dimensional echocardiographic study. Am Heart J, 135, 937-944). The first abnormality described is infero-lateral hypokinesia. This is followed by LV dilatation and a reduction in fractional shortening and ejection fraction. Diastolic dysfunction has also been reported in the early stages of the disease (Heymsfield S B, McNish T, Perkins J V, Feiner J M. (1978) Sequence of cardiac changes in Duchenne muscular dystrophy. Am Heart J, 95, 283-294; Kermadec J M, et al. (1994) Prevalence of left ventricular systolic dysfunction in Duchenne muscular dystrophy: an echocardiographic study. Am Heart J, 127, 618-23).
Since the genetic abnormality is present from birth, it can be assumed that ventricular abnormalities in myocardial function are present earlier in life but are not detected using the conventional imaging techniques. Ultrasound tissue characterization, using integrated backscatter, has recently shown evidence for early changes in myocardial ultrastructure prior to development of clinical cardiac involvement (Giglio V, et al. (2003) Ultrasound tissue characterization detects preclinical myocardial structural changes in children affected by Duchenne muscular dystrophy. J Am Coll Cardiol, 24, 309-316). Using Doppler Myocardial velocity Imaging (DMI), a new non-invasive cardiac imaging technique that allows the quantification of regional myocardial function, we have recently shown the presence of regional myocardial dysfunction in young DMD children (aged 3-10 yrs) without cardiac symptoms and with yet normal global cardiac function as assessed by conventional echocardiography (Mertens L, et al. (2004) Early detection of regional myocardial dysfunction in Duchenne muscular dystrophy by ultrasonic strain and strain rate imaging. Neuromusc Disorders, 14: 599-600). With DMI, regional function is assessed by measuring tissue velocities and calculating the cardiac deformation properties regional strain rate and strain (Sutherland G R, et al. (2004) Strain and Strain Rate Imaging: A New Clinical Approach to Quantifying Regional Myocardial Function. J Am Soc Echocardiogr. 17:788-802; Weidemann F, Eyskens B, Sutherland G R. (2002) New ultrasound methods to quantify regional myocardial function in children with heart disease. Pediatr Cardiol, 23: 292-306). Compared to normal controls, in young DMD patients we found a significant decrease in radial peak systolic strain rate and strain in the inferolateral (posterior) wall, and in longitudinal peak systolic strain rate and strain in the segments of the LV lateral wall. Recently, it was demonstrated that strain rate is predictive of deterioration in cardiac function and death in children with Duchenne muscular dystrophy, who at the time of the baseline measurement were asymptomatic with normal echocardiographic measures of cardiac function (Giatrokos N. et al.; Strain rate can accurately predict a more aggressive cardiac involvement in asymptomatic patients with Duchenne muscular dystrophy Circulation, November 2004, Supplement).
Pharmacological intervention for the treatment of DMD-associated muscle weakness is currently confined to the use of glucocorticoids such as prednisone or deflazacort. It is well documented that glucocorticoids slow down the loss of muscle mass in DMD patients thus acting as potentially disease-modifying compounds. For example, increased muscle strength has been seen in controlled clinical trials where young DMD patients were treated with glucocorticoids, such as 6α-methylprednisolone-21 sodium succinate (PDN) or deflazacort (Fenichel G M, et al. (1991) Long-term benefit from prednisone therapy in Duchenne muscular dystrophy. Neurology; 41:1874-1877; Reitter B. (1995) Deflazacort vs. prednisone in Duchenne muscular dystrophy: trends of an ongoing study. Brain Dev; 17:39-43; Bonifati M D, et al. (2000) A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Muscle Nerve 23:1344-1347). Although trials with daily prednisone or deflazacort have demonstrated increased muscle strength/performance and slowed progression of weakness, as yet there is no universal consensus regarding the use of corticosteroids as standard treatment for DMD. Reasons for this are the lack of sufficient comparative data on the effects of long-term treatment and on the side effects profile in these children. Side effects reported in available clinical trials were weight gain and development of cushinoid facial appearance. However, other side effects have been reported or are major concerns in clinical practice: decreased linear growth, cataracts, osteoporosis and pathological fractures, and behavioral changes. Conclusions of a recent review of available evidence on corticosteroids in DMD were as follows: prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be offered as treatment, benefits and side effects should be monitored, and the offer of treatment with corticosteroids should include a balanced discussion of potential risks (Moxley R T, et al. (2005) Practice Parameter Corticosteroid treatment of Duchenne dystrophy. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 64:13-20). Nevertheless, important questions or issues such as when to start corticosteroid treatment, and fear of significant side effects on the long-term remain. Currently, efforts both in the USA and in Europe are ongoing or being developed to identify which of the many different corticosteroid regimens would be most beneficial with the least of side effects. Few data have been reported suggesting a possible cardioprotective effect of deflazacort (Silversides C K, et al. (2003) Effects of deflazacort on left ventricular function in patients with Duchenne muscular dystrophy. Am J Cardiol 91(6):769-772), but more studies are required as it remains largely unknown whether the use of corticosteroids (targeted to improve skeletal muscle function) could have beneficial or negative effects on the heart in DMD patients.
Dilated cardiomyopathy associated with DMD, BMD and XLMD is currently treated only in advanced stages when symptomatic heart failure becomes apparent or if echocardiographically significant systolic dysfunction is observed that deteriorates progressively. In these circumstances, i.e. at the clinical evident state, clinical practice uses angiotensin converting-enzyme (ACE) inhibitors, beta-blockers or diuretics (Finsterer J., Stöllberger C. (2000) Cardiac involvement in primary myopathies. Cardiology 94:1-11; Bushby K, Muntoni F, Bourke J P. (2003) 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. Neuromusc Disorders 13(2):166-172). These pharmacological interventions are not targeting the cause or specific pathophysiological cellular processes in the cardiomyocytes that underlie the dilated cardiomyopathy associated with DMD/BMD/XLMD. Consequently, their outcome is considered to be limited, and there is a need for the development of new therapeutic interventions specifically targeting the diseased cardiomyocytes in these disorders.
Accordingly, there is a strong need in the art to provide further means for treating and/or preventing several symptoms associated with muscular dystrophies. Said object is achieved by providing idebenone for preparing a medicament for treating and/or preventing weakness and loss of skeletal muscle tissue and/or cardiomyopathies associated with muscular dystrophies.